CAREER: Mechanistic Studies of Tyrosine Derived Cofactors

职业：酪氨酸衍生辅因子的机制研究

• 批准号: 0747377
• 负责人: Minae Mure
• 金额: $ 70万
• 依托单位: University of Kansas Center for Research Inc
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0747377&HistoricalAwards=false
• 关键词: CAREER; Mechanistic; Studies; Tyrosine; Derived

Copper amine oxidase (CAO) and lysyl oxidase (LOX) belong to a family of proteins that contain quinone cofactors that are formed post-translationally from tyrosine, 2,4,5-trihydroxy-phenylalanine quinone (TPQ), and lysine tyrosylquinone (LTQ), respectively. These enzymes catalyze the modification of biogenic amines and play roles in cell signaling and collagen formation. The structure/function study of these quinone cofactors is essential to characterize the differences in their chemical properties. Although the chemical function of TPQ in CAO catalysis has been well studied, very little is known about LTQ. Further, the role of copper in catalysis in both enzymes remains unclear. The research project will further define the chemical properties of TPQ and LTQ and the role of copper in CAO catalysis, as well as develop a model system to understand the chemical function of LTQ in LOX. The research utilizes the tools and techniques of biochemistry, molecular biology, bioinorganic and synthetic organic chemistry. The results of this research will not only broaden understanding of quinoproteins but also impact fundamental understanding of other cross-linked quinones that are widely found in nature. This will aid in understanding the evolutionary advantage of selecting one quinone cofactor over the other in biological systems.Broader Impact: This multidisciplinary project provides an excellent opportunity for graduate and undergraduate students to study at the interface of chemistry and biology and participate in an international collaboration. An outreach program will be initiated to invite female students from local high schools to spend two weeks in the Chemistry department at the University of Kansas. The students will work in the laboratory and meet with female faculty and graduate students to discuss both science and the issues facing women in chemistry. These experiences are intended to encourage more women to follow careers in chemistry by demonstrating at the outset that the academic environment can be supportive to women. The workshop will also show that chemistry is a diverse subject that is much broader in scope than what would typically be taught in high school. In concert, a chemical biology course targeting upper level undergraduate and graduate students will be developed to demonstrate how chemical methods are used to understand fundamental aspects of biological systems. The course will include protein chemistry, especially post-translational modifications as well as a survey of cutting edge discoveries, intended to show students that chemists can make important contributions at the cutting-edge of biological science. Students participating in the Initiative for Minority Student Development (IMSD)-Bioscience Initiative program at the University of Kansas will be encouraged to enroll in this course. The principal investigator will actively recruit minority undergraduate students through this program into her laboratory to help them in pursuing graduate studies and a research career in the field of chemical biology.

铜胺氧化酶（CAO）和赖氨酸氧化酶（LOX）属于一个含有醌辅助因子的蛋白家族，它们分别由酪氨酸、2,4,5-三羟基苯基丙氨酸醌（TPQ）和赖氨酸酪氨酸醌（LTQ）在翻译后形成。这些酶催化生物胺的修饰，并在细胞信号传导和胶原形成中发挥作用。研究这些醌类辅助因子的结构/功能是表征其化学性质差异的必要条件。虽然TPQ在CAO催化中的化学功能已经得到了很好的研究，但对LTQ的了解甚少。此外，铜在这两种酶的催化作用仍不清楚。本研究项目将进一步明确TPQ和LTQ的化学性质以及铜在CAO催化中的作用，并建立模型系统来了解LTQ在LOX中的化学功能。本研究运用生物化学、分子生物学、生物无机化学和合成有机化学的工具和技术。这项研究的结果不仅将扩大对醌蛋白的认识，而且将影响对自然界中广泛发现的其他交联醌的基本认识。这将有助于理解在生物系统中选择一种醌辅助因子优于另一种的进化优势。更广泛的影响：这个多学科项目为研究生和本科生提供了一个极好的机会，在化学和生物学的界面上学习，并参与国际合作。此外，还将开展邀请当地高中女学生到堪萨斯大学化学系学习两周的拓展活动。学生们将在实验室工作，并与女教师和研究生会面，讨论科学和女性在化学领域面临的问题。这些经历旨在鼓励更多的女性从事化学职业，从一开始就表明学术环境可以支持女性。该研讨会还将表明，化学是一门多元化的学科，其范围比高中通常教授的内容要广泛得多。与此同时，一门针对高年级本科生和研究生的化学生物学课程将被开发出来，以展示如何使用化学方法来理解生物系统的基本方面。本课程将包括蛋白质化学，特别是翻译后修饰，以及对前沿发现的调查，旨在向学生展示化学家可以在生物科学的前沿做出重要贡献。堪萨斯大学鼓励参加少数民族学生发展计划(IMSD)-生物科学计划的学生参加本课程。首席研究员将通过该项目积极招募少数民族本科生进入她的实验室，帮助他们攻读化学生物学领域的研究生和研究事业。